In vitro and in vivo characterization of a novel nonsteroidal, species-specific progesterone receptor modulator, PRA-910.

Z. Zhang, S. G. Lundeen, Ov Slayden, Y. Zhu, J. Cohen, T. J. Berrodin, J. Bretz, S. Chippari, J. Wrobel, P. Zhang, A. Fensome, R. C. Winneker, M. R. Yudt

Research output: Chapter in Book/Report/Conference proceedingChapter

8 Citations (Scopus)

Abstract

The progesterone receptor (PR) is an important regulator of female reproduction. Consequently, PR modulators have found numerous pharmaceutical utilities in women's reproductive health. In the process of identifying more receptor-specific and tissue-selective PR modulators, we discovered a novel nonsteroidal, 6-aryl benzoxazinone compound, PRA-910, that displays unique in vitro and in vivo activities. In a PR/PRE reporter assay in COS-7 cells, PRA-910 shows potent PR antagonist activity with an IC50 value of approximately 20 nM. In the alkaline phosphatase assay in the human breast cancer cell line T47D, PRA-910 is a partial progesterone antagonist at low concentrations and is also an effective PR agonist at higher concentrations (EC50 value of approximately 700 nM). PRA-910 binds to the human PR with high affinity (Kd = 4 nM) and was previously shown to exhibit greater than 100-fold selectivity for the PR versus other steroid receptors. In the adult ovariectomized rat, PRA-910 is a potent PR antagonist. It inhibits progesterone-induced uterine decidual response with an ED50 value of 0.4 mg/kg, p.o., and reverses progesterone suppression of estradiol-induced complement C3 expression with potency similar to RU-486. In the nonhuman primate, however, PRA-910 is a PR agonist. The effect on endometrial histology strongly resembles that of progesterone. This unique compound also suppresses estradiol-induced epithelial cell proliferation and both estrogen and progesterone receptor expression in the uterine endometrium as a PR agonist would. In summary, PRA-910 is a structurally and biologically novel selective PR modulator with either PR agonist or antagonist activity, depending on context, concentration, and species.

Original languageEnglish (US)
Title of host publicationErnst Schering Foundation symposium proceedings
Pages171-197
Number of pages27
Edition1
StatePublished - 2007
Externally publishedYes

Fingerprint

Progesterone Receptors
Progesterone
In Vitro Techniques
PRA-910
Estradiol
Benzoxazines
Mifepristone
Complement C3
Steroid Receptors
COS Cells
Reproductive Health
Women's Health
Endometrium
Estrogen Receptors
Primates
Inhibitory Concentration 50
Reproduction
Alkaline Phosphatase
Histology
Epithelial Cells

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Zhang, Z., Lundeen, S. G., Slayden, O., Zhu, Y., Cohen, J., Berrodin, T. J., ... Yudt, M. R. (2007). In vitro and in vivo characterization of a novel nonsteroidal, species-specific progesterone receptor modulator, PRA-910. In Ernst Schering Foundation symposium proceedings (1 ed., pp. 171-197)

In vitro and in vivo characterization of a novel nonsteroidal, species-specific progesterone receptor modulator, PRA-910. / Zhang, Z.; Lundeen, S. G.; Slayden, Ov; Zhu, Y.; Cohen, J.; Berrodin, T. J.; Bretz, J.; Chippari, S.; Wrobel, J.; Zhang, P.; Fensome, A.; Winneker, R. C.; Yudt, M. R.

Ernst Schering Foundation symposium proceedings. 1. ed. 2007. p. 171-197.

Research output: Chapter in Book/Report/Conference proceedingChapter

Zhang, Z, Lundeen, SG, Slayden, O, Zhu, Y, Cohen, J, Berrodin, TJ, Bretz, J, Chippari, S, Wrobel, J, Zhang, P, Fensome, A, Winneker, RC & Yudt, MR 2007, In vitro and in vivo characterization of a novel nonsteroidal, species-specific progesterone receptor modulator, PRA-910. in Ernst Schering Foundation symposium proceedings. 1 edn, pp. 171-197.
Zhang Z, Lundeen SG, Slayden O, Zhu Y, Cohen J, Berrodin TJ et al. In vitro and in vivo characterization of a novel nonsteroidal, species-specific progesterone receptor modulator, PRA-910. In Ernst Schering Foundation symposium proceedings. 1 ed. 2007. p. 171-197
Zhang, Z. ; Lundeen, S. G. ; Slayden, Ov ; Zhu, Y. ; Cohen, J. ; Berrodin, T. J. ; Bretz, J. ; Chippari, S. ; Wrobel, J. ; Zhang, P. ; Fensome, A. ; Winneker, R. C. ; Yudt, M. R. / In vitro and in vivo characterization of a novel nonsteroidal, species-specific progesterone receptor modulator, PRA-910. Ernst Schering Foundation symposium proceedings. 1. ed. 2007. pp. 171-197
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abstract = "The progesterone receptor (PR) is an important regulator of female reproduction. Consequently, PR modulators have found numerous pharmaceutical utilities in women's reproductive health. In the process of identifying more receptor-specific and tissue-selective PR modulators, we discovered a novel nonsteroidal, 6-aryl benzoxazinone compound, PRA-910, that displays unique in vitro and in vivo activities. In a PR/PRE reporter assay in COS-7 cells, PRA-910 shows potent PR antagonist activity with an IC50 value of approximately 20 nM. In the alkaline phosphatase assay in the human breast cancer cell line T47D, PRA-910 is a partial progesterone antagonist at low concentrations and is also an effective PR agonist at higher concentrations (EC50 value of approximately 700 nM). PRA-910 binds to the human PR with high affinity (Kd = 4 nM) and was previously shown to exhibit greater than 100-fold selectivity for the PR versus other steroid receptors. In the adult ovariectomized rat, PRA-910 is a potent PR antagonist. It inhibits progesterone-induced uterine decidual response with an ED50 value of 0.4 mg/kg, p.o., and reverses progesterone suppression of estradiol-induced complement C3 expression with potency similar to RU-486. In the nonhuman primate, however, PRA-910 is a PR agonist. The effect on endometrial histology strongly resembles that of progesterone. This unique compound also suppresses estradiol-induced epithelial cell proliferation and both estrogen and progesterone receptor expression in the uterine endometrium as a PR agonist would. In summary, PRA-910 is a structurally and biologically novel selective PR modulator with either PR agonist or antagonist activity, depending on context, concentration, and species.",
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AU - Zhu, Y.

AU - Cohen, J.

AU - Berrodin, T. J.

AU - Bretz, J.

AU - Chippari, S.

AU - Wrobel, J.

AU - Zhang, P.

AU - Fensome, A.

AU - Winneker, R. C.

AU - Yudt, M. R.

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N2 - The progesterone receptor (PR) is an important regulator of female reproduction. Consequently, PR modulators have found numerous pharmaceutical utilities in women's reproductive health. In the process of identifying more receptor-specific and tissue-selective PR modulators, we discovered a novel nonsteroidal, 6-aryl benzoxazinone compound, PRA-910, that displays unique in vitro and in vivo activities. In a PR/PRE reporter assay in COS-7 cells, PRA-910 shows potent PR antagonist activity with an IC50 value of approximately 20 nM. In the alkaline phosphatase assay in the human breast cancer cell line T47D, PRA-910 is a partial progesterone antagonist at low concentrations and is also an effective PR agonist at higher concentrations (EC50 value of approximately 700 nM). PRA-910 binds to the human PR with high affinity (Kd = 4 nM) and was previously shown to exhibit greater than 100-fold selectivity for the PR versus other steroid receptors. In the adult ovariectomized rat, PRA-910 is a potent PR antagonist. It inhibits progesterone-induced uterine decidual response with an ED50 value of 0.4 mg/kg, p.o., and reverses progesterone suppression of estradiol-induced complement C3 expression with potency similar to RU-486. In the nonhuman primate, however, PRA-910 is a PR agonist. The effect on endometrial histology strongly resembles that of progesterone. This unique compound also suppresses estradiol-induced epithelial cell proliferation and both estrogen and progesterone receptor expression in the uterine endometrium as a PR agonist would. In summary, PRA-910 is a structurally and biologically novel selective PR modulator with either PR agonist or antagonist activity, depending on context, concentration, and species.

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